Can red yeast rice & olive extract improve lipid profile and cardiovascular risk in metabolic syndrome? A double blind randomized controlled trial

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1 Can red yeast rice & olive extract improve lipid profile and cardiovascular risk in metabolic syndrome? A double blind randomized controlled trial Prof. Dr. N. Hermans Department of Pharmaceutical Sciences, Research Group NatuRA Prof. Dr. V. Verhoeven Faculty of Medicine, Research Group ELIZA

2 Introduction 1

3 Outline Introduction Aim Material & methods - Study design - Biomarkers of metabolic stress - Biomarkers of oxidative stress Results Discussion Conclusion 2

4 Alberti et al., Circulation,120,2009 Introduction 3

5 Introduction

6 Introduction STATINS HMGCoA-reductase inhibitors 5 Rang and Dale s Pharmacology, 6th ed., 2007

7 Aim Double blind placebo controlled randomized trial to study the efficacy of red yeast rice (RYR) olive fruit extract on 1. LDL and oxidative stress 2. serum lipid parameters, blood pressure, cardiovascular risk, side effects 6

8 Outline Introduction Aim Material & methods - Study design - Biomarkers of metabolic stress - Biomarkers of oxidative stress Results Discussion Conclusion 7

9 Material & Methods Study design Double blind Placebocontrolled N=50 Metabolic syndrome: NCEP ATP III + LDL > 160 mg/ dl RYR-olive Placebo 8 weeks N=26 N=24 Biomarkers of metabolic syndrome Biomarkers of oxidative stress 8

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12 Material & Methods Study design Clinical parameters Waist circumference BMI Blood pressure Biochemical parameters Total Cholesterol LDL HDL apoa1 apob Triglycerides HbA1c 11

13 Material & Methods Study design Parameters of oxidative stress Oxidised LDL (OxLDL) Malondialdehyde (MDA) Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) 12

14 Material & Methods Biomarkers of oxidative stress MDA Oxidative degradation PUFA Plasma λ(ex) = 532 nm λ(em) = 553 nm 13

15 Material & Methods Biomarkers of oxidative stress OxLDL Plasma OxLDL ELISA (Mercodia) Lp-PLA 2 Plasma Lp-PLA 2 activity (PLAC-test) 14

16 Material & Methods RYR-olive fruit extract Red yeast rice (RYR) Asia - traditional medicine - used in food as food colorant, flavour enhancer Fermentation of rice by Monascus purpureus: secondary metabolites : monacolins 15

17 Material & Methods RYR-olive fruit extract Red yeast rice (RYR) 10 mg monacolin K Inhibition HMG-CoA reductase 2 forms BIOLOGICAL ACTIVITY lovastatin 16

18 Material & Methods RYR-olive fruit extract Olive fruit extract Main polyphenolic constituents: Antioxidative activity ê oxidation of LDL 10 mg hydroxytyrosol 17

19 Material & Methods RYR-olive fruit extract Olive fruit extract ê oxidation of LDL EFSA, EFSA Journal, 9, 2033 (2011) 18

20 Randomised Controlled Trials - 1 RCT, cross-over, multicenter, 3 weeks (200 men) 25 ml/day of olive oil: Material & Methods RYR-olive fruit extract Quantified on main polyphenols LOW PC: 2.7 mg/kg polyphenols no HO-tyrosol MEDIUM PC: 164 mg/kg polyphenols 28.5 mg/kg HO-tyrosol HIGH PC: 366 mg/kg polyphenols 63.5 mg/kg HO-tyrosol Biomarkers of lipid peroxidation Dose-effect relationship Weinbrenner et al., J Nutr, 134, (2004); Covas et al., Ann Intern Med, (2006) 19

21 Dose-effect relationship Material & Methods RYR-olive fruit extract LOW PC: 2.7 mg/kg polyphenols no HO-tyrosol MEDIUM PC: 164 mg/kg polyphenols 28.5 mg/kg HO-tyrosol HIGH PC: 366 mg/kg polyphenols 63.5 mg/kg HO-tyrosol polyphenols, HO-tyrosol antioxidant activity Lipid peroxidation 20

22 Dose-effect relationship Material & Methods RYR-olive fruit extract VOO (Virgin olive oil): ROO (Refined olive oil): 629 mg/l polyphenols - 24,4 mg/l tyrosol; 63,5 mg/l hydroxytyrosol; 327,2 mg/l oleuropein derivatives 0 mg/l polyphenols 21 de la Torre-Carbot et al., J Nutr, 140, (2010)

23 Material & Methods Analysis of test product Monacolin K Lovastatin HPLC-UV analysis of RYR ± 0.84 mg monacolins/caps 22

24 Material & Methods Analysis of test product Hydroxytyrosol HPLC-UV analysis of hydroxytyrosol 9.32 ± 0.54 mg / caps hydroxytyrosol 23

25 Outline Introduction Aim Material & methods - Study design - Biomarkers of metabolic stress - Biomarkers of oxidative stress Results Discussion Conclusion 24

26 Results - biochemical Table 1: Comparison between alterations in biochemical parameters in intervention and control group 25

27 Results Clinical Table 2: Comparison between alterations in clinical parameters in intervention and control group 26 Verhoeven et al., BMC Complem. Altern. Med., 2015

28 Results Biomarkers of oxidative stress MDA Plasma MDA-levels at baseline & after 8 weeks of treatment in RYR-olive treated & placebo groups. 27 Hermans et al., J Funct Foods,submitted for public (2015)

29 Results Biomarkers of oxidative stress OxLDL 20% Plasma OxLDL-levels at baseline & after 8 weeks of treatment in RYRolive treated & placebo groups. ***: p<0,001 mean difference placebo-intervention groups. 28 Hermans et al., J Funct Foods,submitted for public (2015)

30 Results Biomarkers of oxidative stress Lp-PLA 2 7% Plasma Lp-PLA 2 -levels at baseline & after 8 weeks of treatment in RYR-olive treated & placebo groups. ***: p<0,001 mean difference placebo-intervention groups. 29 Hermans et al., J Funct Foods,submitted for public (2015)

31 Results Biomarkers of oxidative stress r=0,740 n=26 p<0,001 Correlation between the absolute difference in OxLDL & Lp-PLA2. 30

32 Results Cardiovascular risk Median CV risk in both groups: 2% Intervention group: 1-18% Control group: 1-46% After the intervention: lower risk in 8/26 in RYR-olive (mainly blood pressure) lower risk in 1/24 higher risk in 2/24 in control group 31

33 Outline Introduction Aim Material & methods - Study design - Biomarkers of metabolic stress - Biomarkers of oxidative stress Results Discussion Conclusion 32

34 Discussion RYR - olive (Monakolin K 10 mg; Hyroxytyrosol 10 mg) daily 8 weeks Total cholesterol ê 17 % LDL ê 24 % Triglyceride ê 9 % Blood pressure ê 7 % (10 mmhg) systolic 9 % (7 mmhg)diastolic OxLDL ê 20 % Lp-PLA2 ê 7 % 33

35 Discussion Study Type Aim N Dose Results Conclusion Heber et al., Am J Clin Nutr 1999 RCT-DB, 12 w Cholesterollowering effects of RYR compared to diet 83 2,4 g/dg RYR (~ 10mg MK) Reduction of LDL, TC, TG Significant reduction of TC, TG en LDL. Lin et al., Eur J Endocrinol 2005 RCT DB, 8 w Lipid lowering effects and safety of RYR 79 1,2 g/dg RYR (~11,5 mg MK) LDL: -28% TC: -22% TG: -16% HDL: NS Significant reduction of LDL, TC en TG. Well tolerated Tetsuo et al RCT DB, 8 w Dose-effect study of RYR mg RYR (= 2 mg MK), 200mg RYR (= 4 mg MK) 100mg RYR: LDL: -17% TC: -9% 200mg RYR: LDL: -17% TC: -12% 100 mg RYR (2mg MK)/day: reduction of LDL en TC. 34

36 Discussion Study Type Aim N Dose Results Conclusion Gheith et al., Ind J Nephrol 2008 Open label, 12 m Efficacy and safety of RYR compared to fluvastatin in treatment of nephrotic dyslipidemia 72 0,6 g RYR 2x/day 20 mg statin/day TC fluva: -31% TC RYR: -54% Proteinuria Safe and effective in treatment of nephrotic dyslipidemia Liu et al., Am J Cardiol, 2008 RCT 4,5 j Effect of XZK in secondary prevention of AMI ,3 g XZK (= 2,5 3,2 mg MK) TC: -11% LDL: -18% (8w) XZK: reduced cholesterol level, 30% coronary events and mortality Mitchell et al., J Clin Lipidol 2012 RCT DB, 12 m Cholesterol lowering effects of nutritional drink with or without RYR 79 0,6 g/dg RGR (2,4 mg MK) drink with RYR: at 8w, TC: -14% at 8w, LDL: -8% RYR containing drink lowers LDL en TC. Well tolerated. 35

37 Discussion Statin intolerant (SAM) patients Study Type Aim N Dose Results Conclusion Venero et al., Am J Cardiol, 2010 > 4 w Dose-effect study and tolerance of RYR 25 1,2 g/day RYR TC: -15% LDL: -21% TGs: -6% HDL: -0,5% Mild reduction of TC and LDL. well-tolerated Becker et al., Ann Intern Med, 2009 RCT DB 24 w Effectivity and tolerance 62 3,6 g/dg RYR (3,6 mg MK) LDL: -21% vs placebo Therapeutic option for patients with SAM 36

38 Discussion- side effects 20/26 in intervention group: no side effects 21/24 participants in placebo group: no side effects Side effects Intervention group (26) Placebo group (24) Muscle ache 3 1 Muscle cramps 1 1 Muscle weakness 1 1 Arthralgia 1 2 Mild CK elevation (less than twice the cut off) was present in 4/26 vs 2/24. 37

39 Discussion - Challenges Treatment > 8 weeks > study population / statin intolerant patients Effect due to combination RYR-olive extract? synergistic,?? à Biomarkers of oxidative stress Quality: Batch control!! - monacolin K levels monacolin K/lovastatin ratio - hydroxytyrosol levels - citrinin 38

40 Discussion Citrinin? Mycotoxin formed during fermentation of rice may also be formed in stored grains & other plant food products (beans, fruits, spoiled dairy products, herbs & spices, ) Optimisation of RYR fermentation process: citrinin Nephrotoxic? Level of no concern for nephrotoxicity : < 0.2 µg/kg b.w. EC Regulation 212/2014 : max 2000 µg/kg RYR Screening of citrinin in RYR of study: <2.5 µg/kg RYR APB : screening RYR supplements on Belgian market : no significant contamination with citrinin 39 EFSA Journal 2012;10(3):2605; EC 212/2014

41 Conclusion RYR - olive extract (Monakolin K 10 mg; Hyroxytyrosol 10 mg) daily 8 weeks Total cholesterol ê 17 %, LDL ê 24 %, Triglyceride ê 12 % Blood pressure ê 10 mmhg systolic ê 7 mmhg diastolic Anti-oxidative : OxLDL ê 20 %, Lp-PLA2 ê 7 % << long term studies 4.5 years secondary prevention - coronary events/ mortality Liu et al.(2008) Well-tolerated statin intollerant patients? >> RCT in statin intollerant patients long-term Case reports Vercelli et al., J Am Geriatr Soc (2006); Mueller PS, Ann Int med, (2006); Prasad et al., Transplantation, (2002) 40

42 Acknowledgement Faculty of Medicine ELIZA Prof. Dr. V. Verhoeven Department of Pharmaceutical Sciences NatuRA Natural Products & Food Research and Analysis LEMP Prof. Dr. L. Van Gaal Prof. Dr. S. Apers Dr. A. Breynaert PhDs A. Van der Auwera 41

43 Thank you for your attention 42